ClinVar Miner

Submissions for variant NM_002524.5(NRAS):c.34G>A (p.Gly12Ser) (rs121913250)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212761 SCV000208917 pathogenic not provided 2018-07-02 criteria provided, single submitter clinical testing This variant is denoted p.Gly12Ser (GGT>AGT): c.34 G>A in exon 2 of the NRAS gene (NM_002524.3). G12S has been reported as a germline variant in two neonates with a severe RASopathy phenotype (Mason-Suares et al., 2017) and in a child with juvenile myelomonocytic leukemia (JMML) (Holmfeldt et al., 2013). However, G12S and other missense variants at this residue are most frequently reported as somatic variants in patients with JMML (Matsuda et al., 2007) and other hematopoietic and lymphoid types of cancer (Catalogue of Somatic Mutations in Cancer; Cirstea et al., 2010). The G12S variant is not observed in large population cohorts (Lek et al., 2016). The variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. The glycine codons 12 and 13 of RAS proteins within the RAS/MAPK pathway are functionally important for GDP/GTP binding and are considered hot spots" for pathogenic variants (Wey et al. 2013; Gripp et al. 2012). Missense variants in the same residue (G12C/R/D/A) have been observed at GeneDx in patients referred for NRAS gene analysis. A nearby residue (G13D) has been reported in the Human Gene Mutation Database in association with NRAS-related disorders (Stenson et al., 2014). We interpret this variant to be pathogenic."
Invitae RCV001066799 SCV001231819 pathogenic Rasopathy 2019-11-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 12 of the NRAS protein (p.Gly12Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of a RASopathy (PMID: 28098151, 28594414). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 177778). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C5). This variant disrupts the p.Gly12 amino acid residue in NRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21263000, 19966803). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000158978 SCV000204071 pathogenic Juvenile myelomonocytic leukemia; Noonan syndrome 2013-12-02 no assertion criteria provided clinical testing The Gly12Ser variant has been identified by our laboratory in one individual wit h juvenile myelomonocytic leukemia (JMML) and dysmorphic features. In addition, this variant has been reported in 3 other individuals with JMML (Yoshida 2009), and was not identified in large population studies. Functional studies have show n the Gly12Ser variant causes constitutive NRAS signaling in the absence of grow th factor (Cirstea 2010). Computational analyses (biochemical amino acid propert ies, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Gly12Ser var iant may impact the protein, though this information is not predictive enough to determine pathogenicity. Other variants at the Gly12 residue in RAS genes (NRAS , KRAS, HRAS) have been associated with multiple cancers, highlighting the impor tance of this position in cell signaling (Schubbert 2007). While this variant ha s not been identified in individuals with classic features of Noonan syndrome, i t is likely due to the severe impact of the variant. In summary, this variant me ets our criteria for pathogenicity for JMML and Noonan-spectrum disorders (http: //pcpgm.partners.org/LMM).
Database of Curated Mutations (DoCM) RCV000430288 SCV000503746 likely pathogenic Myelodysplastic syndrome 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439216 SCV000503747 pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421993 SCV000503748 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433097 SCV000503749 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442594 SCV000503750 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421327 SCV000503751 pathogenic Non-small cell lung cancer 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431995 SCV000503752 pathogenic Melanoma 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445150 SCV000503753 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427184 SCV000503754 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only

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